Abstracts

Rationale: Intracellular calcium plays an important role in neuronal hyperexcitability that leads to seizures. Transient receptor potential vanilloid type 1 (TRPV1) is a channel with high calcium permeability, and may play a role in the pathogenesis of epilepsy. Here, we evaluated the effects of capsazepine (CPZ), a potent blocker of TRPV1 channels on acoustically evoked seizures (audiogenic seizures, AGS) in the moderate seizure severity sub-strain of genetically epilepsy-prone rat (GEPR-3), a model of inherited epilepsy. Methods: Male and female GEPR-3s were used. For the acute CPZ treatment study, GEPR-3s were tested for AGS susceptibility before and after treatment with various doses of CPZ (0, 1, 3, and 10 mg/kg; i.p.). For semi-chronic CPZ treatment, GEPR-3s were tested for AGS susceptibility before and after 5-day CPZ treatment at the dose of 1 mg/kg (i.p.). The prevalence, latency, and severity of AGS were recorded and analyzed. GEPR-3s were humanely euthanized at the completion of the experiments. Results: We found that CPZ treatment reduced the seizure severity (at the dose of 1 and 3 mg/kg), and suppressed the seizure susceptibility (at the dose of 10 mg/kg) in male GEPR-3s. Interestingly, CPZ treatment at all tested doses (1, 3, and 10 mg/kg) completely suppressed seizure susceptibility in female GEPR-3s. Conclusions: These findings suggest that TRPV1 channel may be a promising molecular target for seizure suppression, with female GEPR-3s exhibiting higher sensitivity than male GEPR-3s. Funding: Public Health Service grants AA020073 (P.N.) from the National Institutes of Health (NIH)